The cockatrice traces its lineage to the basiliskos, a creature first described by Greek travellers and naturalists who journeyed to the deserts of Libya and Egypt. The word basiliskos means Little King in Greek, and the creature earned its title because it was said to bear a white marking upon its head that resembled a crown, and because all other serpents fled from its presence as subjects flee from a monarch. The Greeks believed it was native to Cyrene, a Greek colony on the coast of Libya, and that it haunted the dry wadis and sun-baked rocks where no other creature dared to go. It was small, no longer than a man's forearm, but its venom was so concentrated that a single drop could kill a horse, and its gaze was fatal to any living thing that met it.

The defining features of the cockatrice were catalogued by Greek and Roman writers who drew on earlier travellers' tales. Pliny the Elder, the Roman naturalist who died in the eruption of Mount Vesuvius, recorded in his Natural History that the basilisk was born from the egg of an old rooster, incubated by a serpent or a toad in the dung of cattle. When it hatched, it had the body of a serpent, the head and comb of a rooster, and sometimes the wings of a bat or a dragon. Its breath was a poison so potent that it withered every plant it touched, turned water to venom, and split stones with its acrid fumes. Aelian, the Greek writer who compiled a book on animals in the 2nd century CE, added that the basilisk could be killed only by the ichneumon, a small creature the Greeks called the Egyptian mongoose, which would roll in mud to armour itself against the venom and then attack the serpent-king from behind.

The cockatrice migrated from the pages of Greek and Roman natural history into the Bible and the medieval bestiary. The King James translators of the Bible rendered the Hebrew word tsepha as cockatrice in the book of Isaiah, where the prophet wrote that the cockatrice would emerge from its egg and the viper would hatch from its den. Medieval bestiaries seized upon this authority and placed the cockatrice among the most terrible of God's creatures. Bartholomaeus Anglicus, the 13th-century Franciscan encyclopaedist, described it in his De Proprietatibus Rerum as a serpent with a rooster's head that could kill a man with its breath alone. The Aberdeen Bestiary, a 12th-century illuminated manuscript, painted it as a crowned serpent with wings and a rooster's beak, and warned that its gaze was so deadly that even its reflection in a mirror could kill it.

The methods of killing a cockatrice were as strange as the beast itself. Some said it could be slain only by the ichneumon, the mongoose that the Greeks had described. Others said that a weasel, the ichneumon's European cousin, could defeat it if the weasel first ate rue, a bitter herb that protected it from the venom. Still others claimed that the cockatrice would die if it saw its own reflection in a mirror, perishing by the same power that it used to kill its victims. In heraldry, the cockatrice became a symbol of terror and vigilance, its image placed on shields and banners to warn enemies that the bearer possessed a deadly and unforgiving power. By the Renaissance, the creature had become a fixture of natural history, and the English naturalist Edward Topsell devoted pages to it in his History of Four-Footed Beasts, treating it as a real animal that had simply not been seen by modern scholars.